The objective of this application is to better understand the beneficial effects and protective mechanisms of the mitochondria (mt)-targeted small molecule SS31 and the mt division inhibitor 1 (Mdivi-1) in Alzheimer?s disease (AD). Several lines of evidence suggest that age- and amyloid beta (A?)-induced reactive oxygen species (ROS) is associated with mt and synaptic damage in AD: gene expression studies of AD mouse models have found abnormal mt gene expressions and mtDNA defects in AD neurons, and studies of postmortem AD brains and neurons from AD mice lines have shown abnormalities in mt structure and function. Several studies found that A? is associated with mt and with increased levels of ROS production and mt dysfunction, suggesting that A? may be a key factor in mt dysfunction and neuronal damage. Based on these observations, targeting mt ROS may be an important therapeutic approach to slowing AD progression. However, clinical trials of AD patients to determine the capability of natural antioxidants, including VitC, VitE, beta-carotene, and melatonin to slow disease progression, have yielded limited success, but the research did reveal critical information: that natural antioxidants are not capable of crossing the blood brain barrier and are not capable of reaching mt and so cannot protect mt and synapses in AD neurons. To overcome this challenge, mt-targeted molecule SS31 was developed and has been proven to cross the blood brain barrier in mouse models. However, its efficacies have not been studied preclinically in AD mouse models and clinically in AD patients. Further, in other studies of AD disease progression, defective mt dynamics (increased fission and decreased fusion) were found in AD neurons. Results from preliminary studies revealed that the fission protein Drp1 interacts with A? and phosphorylated tau, resulting in excessive mt fragmentation, increased ROS production, defective transport of mt to synapses, low synaptic ATP, and synaptic dysfunction. Preliminary high throughput studies found that Mdivi-1 reduces excessive mt fragmentation and increases mt fusion in cell models of AD, suggesting that Mdivi-1 is a promising drug to treat AD. The objectives of our R01 application are to determine protective effects SS31 (Aim 1), Mdivi1 (Aim 2), SS31+Mdivi1 (Aim 3), and neuroprotective mechanisms of Mdivi-1 and SS31 (Aim 4) in APP and tau mouse models of AD and non-transgenic WT mice, at 2 stages (preventive and curative) of disease progression. Using state-of-the-art methods, mt structural and functional changes, A? and tau pathologies, and synaptic alterations will be studied in SS31-, Mdivi1-, SS31+Mdivi-1-treated and untreated APP and tau mice and non-transgenic WT mice. Further, protective mechanisms of Mdivi-1 and SS31 will be studied in APP and tau mice. The outcomes of the proposed research will take researchers closer to developing therapeutic approaches capable of slowing or preventing AD progression ? and, ultimately, of curing AD.